Fetal growth is a complex process involving multiple environmental and genetic factors. Fetal growth restriction is associated with severe morbidity among small for gestational age (SGA) neonates as well as in children and adults who are former SGA infants. Over the last decade it has been recognized that the insulin-like growth factors (IGFs) have a critical role in mediating fetal and postnatal growth. However, how these hormones are involved in common pathological processes, leading to fetal growth restriction (FGR), remains unknown. In humans and mice, mutations or targeted deletions of the IGF ligands lgf1 and lgf2, as well as the IGF receptor lgfr1 and its main signaling molecule lrs1 lead to FGR. Furthermore, we and others have shown that cord blood levels of IGFs are low in human SGA newborns; however, only a small minority of these infants have mutations of IGF-related molecules, rather, idiopathic or maternal factors are thought to induce FGR in most of these cases. We have recently demonstrated that lgf2 expression is highly dependent upon epigenetic processes including DNA methylation of specific promotor and imprinting control regions and histone modifications. lgf2 is uniquely expressed through separate transcriptional regulatory control in placental and fetal tissues. We believe that epigenetic processes modulate placental and or fetal /gf2 expression, mediating the process of FGR. Thus, our central hypotheses are that 1) IGF-II plays a critical role in human FGR both as a fetal growth factor as well as a placental growth factor and that 2) environmental factors that lead to FGR affect lgf2 expression via epigenetic mechanisms. To test these hypotheses we plan to: 1) evaluate IGF-II levels and /gf2 expression and epigenetic modification in placentas and cord blood specimens from normal and SGA human newborns, 2) assess IGF-II levels and lgf2 expression and epigenetic modification in fetuses, placentas, and circulation of control and experimental models of rodent maternal-environmental FGR such as uterine artery ligation and protein restriction, and 3) determine the exact role of IGF-II expression and production, in the placenta and fetus, in the growth restriction observed in genetic models of mouse FGR by subjecting genetically altered mice such as /gf2 null mice and the newly developed PAPP-A null mice, that have excess IGFBP-4 and little of no free IGF-II, to experimental FGR protocols. We postulate that environmental causes of FGR act to reduce placental IGF-II levels. We further hypothesize that maternal factors will play a minimal or no additive role beyond genetic ablation or reduction of placental and/or fetal IGF-II. As part of these efforts we will develop new assays for total and free mouse IGF-II. Together, our efforts will serve to validate the role of IGF-II as a central mediator of human FGR and will allow the development of novel diagnostic approaches to identify the pathogenesis of FGR in individual cases as well as to conceptualize new therapeutic directions for this condition.